PROJECT SUMMARY. Neurons regulate synaptic activity by regulating the differentiation of the postsynaptic face of the synapse, including the amount of glutamate receptors that reach the postsynaptic surface. The signaling molecules that regulate glutamate receptor localization need to be completely elucidated to understand postsynaptic differentiation. C. elegans has been an excellent model system for studying glutamate receptors in vivo. The glutamate receptor subunit GLR-1 is required for glutamatergic signaling, and is localized to postsynaptic clusters between C. elegans neurons in a mechanosensory circuit. Using forward genetic screens, we have identified multiple genes that regulate the trafficking of GLR-1 to and from the synapse. One of these genes encodes a PDZ domain protein with orthologs in mammals, and mutations in this gene result in the failure of glutamatergic synapses to recover from habituation. Another of these genes encodes a ubiquitin ligase, and mutations in this gene result in the failure of GLR-1 receptors to be removed from the synapse. We propose three aims for understanding the role of these genes in regulating glutamatergic synapse. First, we will characterize changes in GLR-1 trafficking during habituation and recovery of the mechanosensory circuit. Second, we will characterize the molecular and cell biological function of the ubiquitin ligase with regard to its role in downregulating GLR-1 after habituation. Third, we will characterize the molecular and cell biological function of our PDZ domain protein with regard to its role in upregulating GLR-1 after recovery from habituation. The molecular and cell biological function of these new genes will provide clues to the mechanisms by which glutamate receptors are regulated. RELEVANCE. Many nervous system disorders, including stroke, trauma, ALS, Alzheimers, and Parkinsons, involve the killing of neurons by the neurotransmitter glutamate. High levels of glutamate kill neurons by overactivating their glutamate receptors. It is critical to understand how glutamate receptors are regulated in order to develop novel applications for the diagnosis, treatment, and prevention of neurological disorders, particularly those that stem from glutamate-mediated neurodegeneration.